Ignite Creation Date:
2024-05-06 @ 8:34 AM
Last Modification Date:
2024-10-26 @ 12:02 PM
Study NCT ID:
NCT02766959
Status:
COMPLETED
Last Update Posted:
2018-09-18
First Post:
2016-05-05
Brief Title:
Allele-specific Expression of a Bitter Taste Receptor
Sponsor:
Monell Chemical Senses Center
Organization:
Monell Chemical Senses Center
Study Overview
Official Title:
Bitter Taste and Allele-specific Expression of the Human TAS2R38 Gene
Status:
COMPLETED
Status Verified Date:
2018-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This single-site within-subject experimental basic research study is designed to analyze the hypothesis that allele-specific expression of the bitter taste receptor T2R38 in taste tissue of individuals heterozygous for the taste receptor gene TAS2R38 correlates with that in nasal epithelium and is responsible for differences in acyl-homoserine lactone-induced respiratory defenses Subjects will include 100 predominantly European adults without chronic rhinosinusitis who will be undergoing a sinonasal procedure for reconstructive purposes All subjects will provide saliva samples for genotyping from which 25 subjects heterozygous for TAS2R38 AVIPAV will be identified These individuals will be asked to complete a beverage frequency questionnaire and taste test prior to the procedure that will evaluate for a number of compounds among them bitter ligands specific to T2R38 Their tongue will also be photographed to evaluate the anatomy of their fungiform papillae the mushroom-like structures on the tongue which contain taste buds Subjects will subsequently provide nasal epithelium and taste tissue which will be processed to 1 evaluate for allele-specific expression of TAS2R38 mRNA in both the taste and nasal tissue with the nasal tissue concurrently being cultured in an air-liquid interface system to 2 assess the AHL-induced respiratory defenses of ciliary beat frequency CBF and nitric oxide NO production Should subjects require a subsequent sinonasal procedure for clinically-determined reasons taste and nasal tissue will again be obtained and analyzed for TAS2R38 mRNA allowing for 3 longitudinal evaluation of mRNA expression level
Detailed Description:
The Basic Biology of Bitter Taste The perception of bitter taste is thought to have evolved as a mechanism to protect against the ingestion of toxic materials and is the result of ligand-activation of one of more than 25 different bitter taste receptors so-called T2Rs 1 These receptors are found on the tongue in what are called fungiform papillae mushroom-like structures that contain taste buds with receptors responding to a variety of tastes including sweet salty sour umami and bitter A prototypical example of one of these bitter ligands is phenylthiocarbamide PTC which actives the T2R38 receptor While initially identified in type II taste cells T2R38 is also expressed in nasal epithelium where it participates in innate immune defense responses to invading bacteria 2-6
TAS2R38 A Model System for Genotype-Phenotype Studies Prior studies have identified two main forms of T2R38 active and inactive which are characterized by three genetic variants in the TAS2R38 gene These variants result in three amino acid changes proline P to alanine A at position 49 alanine A to valine V at position 262 and valine V to isoleucine I at position 296 in the T2R38 receptor Individuals who are homozygous for the active PAVPAV form detect bitterness in compounds containing a thiourea -N-CS moiety including PTC 6-n-propylthiouracil PROP and the plant compound goitrin common in foods such as green vegetables 7-9 They also respond to acyl-homoserine lactones AHLs a class of compounds produced as signaling molecules by certain bacteria triggering a rapid defense reaction consisting of increased ciliary beat frequency CBF to facilitate mucociliary clearance and generation of nitric oxide NO a gas that can diffuse into the airway and kill bacteria 4 In contrast those who are homozygous for all three variants AVIAVI consume these compounds without perceiving them as bitter and do not appear to respond to AHLs 10 The frequency of both the active and inactive forms of TAS2R38 is at a near balance of 5050 in many human racial groups including Americans of European and African descent
The Heterozygote Hypothesis Interestingly individuals heterozygous for the active form of the receptor AVIPAV exhibit highly variable phenotypes with some people very sensitive to bitter compounds and others needing high concentrations to taste them at all 11 While the investigators know that taste papillae density plays at least some role in this variability
our preliminary taste data suggest that the range of response is tied to how much mRNA is expressed from the active PAV form of the receptor a concept called allele-specific expression 12 For example this is the case when analyzing caffeine consumption which strongly correlates with active mRNA expression 12 The investigators therefore hypothesize that the abundance of active TAS2R38 mRNA in heterozygous individuals also predicts the biologically significant change in magnitude of defensive responses in the presence of AHLs 13-15 The proposed study will determine whether this is in fact the case and whether those people who have high mRNA abundance in taste tissue fungiform papillae also have correspondingly high abundance in nasal epithelium or whether regulation is tissue-dependent This will allow us to determine whether taste tests could provide a reliable representation of receptor function in other tissues and cell types Should mRNA abundance prove to be a key factor the investigators will determine whether high expressers sustain this expression over time
Of note a study performed by Dr Reed and collaborators found that the population in Philadelphia contained 18 of individuals in the homozygous nontaster AVI group 17 in the homozygous taster PAV group and 37 in the common heterozygous group AVIPAV 16 The remaining 28 were distributed among ten other less common genotypes which will not be analyzed in this study Thus as the majority of the population is heterozygous a thorough understanding of their ability to fight infection is clinically important
Clinical Significance As one of the most common chronic conditions in the United States chronic rhinosinusitis invokes a direct treatment cost of 35-5 billion annually Its incidence is 146 per 1000 and increasing 17 Our prior studies have shown that individuals with two copies of the active form of T2R38 have nasal epithelium that defends very effectively against certain bacteria such as Pseudomonas aeruginosa and are less likely to develop severe chronic rhinosinusitis requiring surgery while those with two inactive forms cannot defend themselves as effectively and are more likely to develop severe chronic rhinosinusitis requiring surgical intervention Because the treatment of chronic rhinosinusitis involves multiple rounds of antibiotics and often surgical management through functional endoscopic sinus surgery FESS this research has significant implications for antibiotic stewardship surgical morbidity and mortality and health care expenditures
TAS2R38 A Model System for Genotype-Phenotype Studies Prior studies have identified two main forms of T2R38 active and inactive which are characterized by three genetic variants in the TAS2R38 gene These variants result in three amino acid changes proline P to alanine A at position 49 alanine A to valine V at position 262 and valine V to isoleucine I at position 296 in the T2R38 receptor Individuals who are homozygous for the active PAVPAV form detect bitterness in compounds containing a thiourea -N-CS moiety including PTC 6-n-propylthiouracil PROP and the plant compound goitrin common in foods such as green vegetables 7-9 They also respond to acyl-homoserine lactones AHLs a class of compounds produced as signaling molecules by certain bacteria triggering a rapid defense reaction consisting of increased ciliary beat frequency CBF to facilitate mucociliary clearance and generation of nitric oxide NO a gas that can diffuse into the airway and kill bacteria 4 In contrast those who are homozygous for all three variants AVIAVI consume these compounds without perceiving them as bitter and do not appear to respond to AHLs 10 The frequency of both the active and inactive forms of TAS2R38 is at a near balance of 5050 in many human racial groups including Americans of European and African descent
The Heterozygote Hypothesis Interestingly individuals heterozygous for the active form of the receptor AVIPAV exhibit highly variable phenotypes with some people very sensitive to bitter compounds and others needing high concentrations to taste them at all 11 While the investigators know that taste papillae density plays at least some role in this variability
our preliminary taste data suggest that the range of response is tied to how much mRNA is expressed from the active PAV form of the receptor a concept called allele-specific expression 12 For example this is the case when analyzing caffeine consumption which strongly correlates with active mRNA expression 12 The investigators therefore hypothesize that the abundance of active TAS2R38 mRNA in heterozygous individuals also predicts the biologically significant change in magnitude of defensive responses in the presence of AHLs 13-15 The proposed study will determine whether this is in fact the case and whether those people who have high mRNA abundance in taste tissue fungiform papillae also have correspondingly high abundance in nasal epithelium or whether regulation is tissue-dependent This will allow us to determine whether taste tests could provide a reliable representation of receptor function in other tissues and cell types Should mRNA abundance prove to be a key factor the investigators will determine whether high expressers sustain this expression over time
Of note a study performed by Dr Reed and collaborators found that the population in Philadelphia contained 18 of individuals in the homozygous nontaster AVI group 17 in the homozygous taster PAV group and 37 in the common heterozygous group AVIPAV 16 The remaining 28 were distributed among ten other less common genotypes which will not be analyzed in this study Thus as the majority of the population is heterozygous a thorough understanding of their ability to fight infection is clinically important
Clinical Significance As one of the most common chronic conditions in the United States chronic rhinosinusitis invokes a direct treatment cost of 35-5 billion annually Its incidence is 146 per 1000 and increasing 17 Our prior studies have shown that individuals with two copies of the active form of T2R38 have nasal epithelium that defends very effectively against certain bacteria such as Pseudomonas aeruginosa and are less likely to develop severe chronic rhinosinusitis requiring surgery while those with two inactive forms cannot defend themselves as effectively and are more likely to develop severe chronic rhinosinusitis requiring surgical intervention Because the treatment of chronic rhinosinusitis involves multiple rounds of antibiotics and often surgical management through functional endoscopic sinus surgery FESS this research has significant implications for antibiotic stewardship surgical morbidity and mortality and health care expenditures
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None